During reproductive ages there is a female preponderance of many autoimmune diseases. In multiple sclerosis (MS) the female to male ratio approaches 2:1. Also, pregnancy has been shown to affect symptomatology of autoimmune diseases. MS is characterized by remission during gestation, and exacerbation during the postpartum period. Thus, a basic question is proposed: How do sex hormones influence immune mechanisms involved in autoimmune mediated demyelinating disease? Experimental autoimmune encephalomyelitis (EAE) is an animal model useful for the study of immune mechanisms in MS. In adoptive EAE in SJL mice, we have recently demonstrated enhanced susceptibility of females as compared to males. The enhanced susceptibility of females was demonstrated in both the induction phase and the effector phase of adoptive EAE. In specific aims #1 and #2, we will determine which immune mechanisms in the induction phase and the effector phase, respectively, are different between genders. Processing of autoantigen, recognition of the antigen/MHC complex and cytokine production by autoantigen specific T lymphocytes (Th1 and Th2 like) will be compared between genders. In specific aims #3 and #4, we will identify the sexhormones responsible for gender related differences in immune mechanisms in the induction phase and the effector phase and the effector phase, respectively. This will be accomplished by implanting female mice with time release hormone pellets (estriol, estradiol, dihydrotestosterone, or placebo) during either the induction phase or the effector phase with subsequent comparisons of immune mechanisms between each hormone treated group. These studies of the effects of sex hormones (endogenous and exogenous) on autoantigen specific immune responses will have therapeutic relevance to MS, and will also provide insight into basic concepts relevant to the enhanced susceptibility of females to autoimmune diseases.